Remimazolam: An Updated Review of a New Sedative and Anaesthetic

Figures & data

Figure 1 The main milestones in the development of remimazolam.

Figure 2 Chemical structures: (A) midazolam, (B) remimazolam besylate, (C) remimazolam tosilate.

Figure 3 Chemical structure of (A) remimazolam and the carboxylic acid metabolite (B) CNS7054.

Table 1 Pharmacokinetic Parameters of Remimazolam and Midazolam

Drug	Onset (Min)	Recovery (Min)	Duration (Min)	CL (L/h)	Vss (L)	T1/2 (Hours)	MRT (Hours)
Remimazolam^Citation17	1–3	5.5–20	8.0	70.3±13.9	34.8±9.4	0.75±0.15	0.51
Midazolam^Citation17,Citation28	3–5	40.0	12.0	23.0±4.5	81.8±27.1	2.89±0.65	3.6

Abbreviations: CL, systemic clearance; Vss, volume of distribution at steady state; T_1/2, terminal half-life; MRT, mean retention time.

Figure 4 The context-sensitive half-times (the time required for the plasma level of the drug to decrease 50% after the infusion is stopped) for the sedatives remimazolam, midazolam, propofol, etomidate, and dexmedetomidine.

Notes: Data from Whizar et al,¹⁰ Wiltshire et al,²² Schüttler et al,²³ and Iirola et al.³³

Table 2 Main Clinical Trials of Remimazolam for Sedation Under Gastroscopy

Author (Year)	Phase	N	Dose of Remimazolam	Age (Years)	Primary Endpoint	Comparator	Co-Treatment	Location (s)	Results
Borkett et al 2019^Citation37	IIa	100	Three dose of group: 0.10, 0.15, or 0.20 mg/kg	18–65	Safety and efficacy of different single doses for sedation in upper gastrointestinal endoscopy	Midazolam 0.075 mg/kg	N/A	USA	A single dose of remimazolam (0.1–0.2mg/kg) was able to induce rapider sedation and faster recovery than midazolam in patients undergoing upper gastrointestinal endoscopy
Chen et al 2021^Citation38	III	384	5.0 mg plus 2.5 top-ups	18–60	Compare efficacy and safety of remimazolam tosilate with propofol for sedation in upper gastrointestinal endoscopy	Propofol 1.5 mg plus 0.5 mg/kg top-ups	Fentanyl (0.5 μg/kg); lidocaine viscous oral liquid 10g	China	The sedation successful rate in remimazolam was non-inferior to propofol but shorter time to recovery from sedation, safety profile appears to be superior to propofol
Tan et al 2022^Citation39	III	99	Initial dose: two dose of group (0.1 mg/kg or 0.2 mg/kg), supplemental dose: 0.05 mg/kg	>60	Efficacy and safety of remimazolam tosilate in patients undergoing bronchoscopy	Propofol 1.0–1.5 mg plus 0.5mg/kg top-ups	N/A	China	A dose of 0.1 mg/kg remimazolam tosilate suitable for sedation in elderly patients undergoing upper gastrointestinal endoscopy
Cao et al 2022^Citation40	III	148	0.107 mg/kg	18–65	Efficacy and safety of remimazolam tosilate sedation in patients with liver cirrhosis undergoing gastroscopy	Propofol 2 mg/kg	Sufentanil 0.15 μg/kg	China	Remimazolam tosilate combined with sufentanil adjuvant is better than propofol with sufentanil in patients with liver cirrhosis undergoing gastroscopy

Abbreviations: N, number of subjects; N/A, not available/applicable.

Table 3 Main Clinical Trials of Remimazolam for Sedation Undergoing Colonoscopy

Author (Year)	Phase	N	Dose of Remimazolam	Age (Years)	Primary Endpoint	Comparator	Co-Treatment	Location (s)	Results
Rex et al 2018^Citation41	III	461	5.0 mg plus 2.5 top-ups	18–74	Efficacy and safety of remimazolam in patients undergoing colonoscopy	Midazolam [1.75 mg plus 0.5 mg (≥60 years) or 1.0 mg (<60 years) top-ups]	Fentanyl (75 μg)	USA	Patients in remimazolam group had Procedural success rate, faster mean procedure time and recovery time, less needed of fentanyl, less incidence of hypotension
Liu et al 2021^Citation42	III	260	0.15mg/kg plus 0.075 mg/kg top-ups	65–75	Efficacy and safety of remimazolam in elderly outpatients undergoing colonoscopy	Etomidate-Propofol (0.1 mL/kg plus 0.05 mL/kg top-ups)	Fentanyl (0.15 mg/kg plus 0.5 mg/kg top-ups, the maximum dose of 150 μg)	China	The procedure success rate in remimazolam group was non-inferior to etomidate-propofol group (96.52% vs 100.00%; difference in rate −3.48%, 95% CI −6.81% to −0.15%), and has a higher safety for elderly patients
Rex et al 2021^Citation43	III	79	2.5–5.0 mg plus 1.25–2.5 mg top-ups	42–84	Safety and efficacy of remimazolam in ASA class III/IV patients undergoing colonoscopy	Midazolam (1.0 mg plus 0.5 mg top-ups)	Fentanyl (50 μg, top up doses of 25 μg, the maximum dose of 200 μg)	USA	Procedure success for patients treated with remimazolam, placebo, midazolam was 87.1%, 0%, 13.3%, the shorter time to sedation and recovery in remimazolam group, and no serious AEs were reported. it can be efficacy and safety for sedation in ASA III/IV patients
Yao et al 2022^Citation44	III	132	0.2 mg/kg plus 6 mg top-ups	18–65	Discharge readiness after remimazolam versus propofol for colonoscopy	Propofol (1 mg/kg plus 30 mg top-ups)	Sufentanil (5 mg)	China	Remimazolam provided a similar sedative efficacy and safer profile in patients undergoing colonoscopy, compared with propofol

Abbreviations: N, number of subjects; N/A, not available/applicable.

Table 4 Main Clinical Trials of Remimazolam for Sedation Under Bronchoscopy

Author (Year)	Phase	N	Dose of Remimazolam	Age (Years)	Primary Endpoint	Comparator	Co-Treatment	Location (s)	Results
Pastis et al 2019^Citation45	III	446	5.0 mg plus 2.5 top-ups	≥18	Safety and efficacy for moderate sedation during bronchoscopy	Midazolam (1–1.75 mg plus 0.5–1.0 mg top-ups)	Fentanyl (25–75 mg, top-up doses of 25 μg, the maximum dose of 200 μg)	USA	Remimazolam achieved moderate procedural sedation efficacy and safety during flexible bronchoscopy, with a rapid onset and rapid return of cognitive function
Jia et al 2021^Citation46	III	50	The first patient was given a dose of 0.18 mg/kg, Maintenance dose: 1mg/kg/h	18–65	Observation of effective dosage of remimazolam tosilate used for moderate sedation in bronchoscopy	N/A	Sufentanil (0.1 μg/kg); 2% lidocaine (5 mL, airway nebulization); flumazenil (0.2 mg)	China	The ED50 and the ED95 of remimazolam tosilate for moderate sedation in bronchoscopy were 0.174 mg/kg and 0.219 mg/kg, combined with Sufentanil 0.1 μg/kg
Chen et al 2022^Citation47	III	146	Initial dose: 12 mg/kg Maintenance dose: 1–2mg/kg/h	45–65	Efficacy and safety of remimazolam tosilate in patients undergoing bronchoscopy	Dexmedeto-midine (0.5 μg/kg, maintained by 0.2–0.7 μg/kg)	Remifentanil (0.05–0.2 μg/kg/min)	China	Remimazolam tosilate has non-inferior efficacy, better time metrics and hemodynamic stability than dexmedetomidine combine with remifentanil in outpatients undergoing bronchoscopy

Abbreviations: N, number of subjects; N/A, not available/applicable.

Table 5 Main Clinical Trials of Remimazolam for Sedation in General Anesthesia

Author (Year)	Phase	N	Dose of remimazolam	Age (years)	Primary endpoint	Comparator	Co-treatment	Location (s)	Results
Doi et al 2020^Citation49	IIb/III	391	Initial dose: 6 mg/kg/h or 12 mg/kg/h Maintenance dose: 1–2 mg/kg/h	≥ 20	Efficacy and safety	Propofol was started at 2.0–2.5 mg/kg, followed by 4–10 mg/kg/h	Remifentanil (0.25 and 0.5 μg/kg/min, maintained by 0.25–2.0 µg/kg/min)	Japan	Remimazolam showed well tolerated and non-inferior to propofol in term of efficacy as a sedative for general anesthesia, but the time to LoC, recovery, and extubation were both longer than propofol
Doi et al 2020^Citation50	III	67	Initial dose: 6 mg/kg/h or 12 mg/kg/h Maintenance dose: 1–2 mg/kg/h	≥ 20	Efficacy and safety	N/A	N/A	Japan	Remimazolam could be used safely and effectively in high-risk surgical patients (ASA Class III), time to LoC was significantly shorter with dose of 12 mg/kg/h
Chae et al 2022^Citation51	III	120	Six dose groups of 0.02, 0.07, 0.12, 0.17, 0.22, and 0.27 mg/kg	>18	Determine the ED50 and ED95 Of IV remimazolam for LoC	N/A	N/A	Korea	A bolus injection of remimazolam can be administered safely without causing significant hemodynamic instability. The optimal doses of 0.25–0.33, 0.19–0.25, and 0.14–0.19 mg. kg-1 in 95% patients aged <40, 60–80, and >80 years
Shimamoto et al 2022^Citation52	N/A	76	Initial dose: 0.2 mg/kg Maintenance dose: 1–2mg/kg/h	20–80	Efficacy and safety	Propofol was started at 2 mg/kg, followed by 4–10 mg/kg/h	Fentanyl citrate (3 μg/kg, maintained by remifentanil 0.25 µg/kg/min)	China	Remimazolam tosilate can provide satisfactory anesthetic effects for EVL and combination with flumazenil can induce quick recovery from anesthesia

Abbreviations: N, number of subjects; N/A, not available/applicable.

Table 6 Main Articles About Other Clinical Application of Remimazolam

Author (Year)	Procedure	Dose	Age (years)	Primary endpoint	Comparator	Co-treatment	Results
Horikoshi et al 2021^Citation59	Single-incision laparoscopic percutaneous extraperitoneal closure in a pediatric with DMD	Induction: 3 mg Maintenance: 15 mg/h	4	Safety	N/A	Fentanyl (100 μg), maintained by remifentanil 1.0 µg/kg/min	Remimazolam can be safely used for general anesthesia in a pediatric patient with DMD
Petkus H et al 2022^Citation58	Dental rehabilitation procedure in a pediatric suspected with family history of MH	5–7 µg/kg/min	6	Safety	N/A	Propofol (50 µg/kg/min)	Remimazolam was effective as an adjunct to propofol during general anesthesia in a pediatric suspected with family history of with MH
Kamata, K et al 2022^Citation60	Supratentorial glioma resection under dc-MEP monitoring	0.9 mg/kg/h	12	Safety	N/A	Remifentanil (0.35 μg/kg/min)	Direct cortical MEP was successfully recorded in the pediatric patient under remimazolam anesthesia with cardiovascular stability
Yamadori, Y et al 2022^Citation61	Open gastrostomy in a pediatric with MELAS	Induction: 0.2 mg/kg Maintenance: 2.0mg/kg/h	10	Safety	N/A	Remifentanil (0.3 μg/kg/min)	Remimazolam could be used in a pediatric with MELAS under general anesthesia without causing seizures and delayed emergence

Abbreviations: ERCP, endoscopic retrograde cholangiopancreatography; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes; DMD, Duchenne muscular dystrophy; N, number of subjects; N/A, not available/applicable.

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